Pleiotropic genomic variants at 17q21.31 associated with bone mineral density and body fat mass: a bivariate genome-wide association analysis

Abstract

Osteoporosis and obesity are two severe complex diseases threatening public health worldwide. Both diseases are under strong genetic determinants as well as genetically correlated. Aiming to identify pleiotropic genes underlying obesity and osteoporosis, we performed a bivariate genome-wide association (GWA) meta-analysis of hip bone mineral density (BMD) and total body fat mass (TBFM) in 12,981 participants from seven samples, and followed by in silico replication in the UK biobank (UKB) cohort sample (N = 217,822). Combining the results from discovery meta-analysis and replication sample, we identified one novel locus, 17q21.31 (lead SNP rs12150327, NC_000017.11:g.44956910G > A, discovery bivariate P = 4.83 × 109, replication P = 5.75 × 105) at the genome-wide significance level (ɑ = 5.0 × 10−8), which may have pleiotropic effects to both hip BMD and TBFM. Functional annotations highlighted several candidate genes, including KIF18B, C1QL1, and PRPF19 that may exert pleiotropic effects to the development of both body mass and bone mass. Our findings can improve our understanding of the etiology of osteoporosis and obesity, as well as shed light on potential new therapies.

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Fig. 1: Manhattan plot.
Fig. 2: Regional plot of rs12150327.
Fig. 3: Gene–gene interaction network for KIF18B, DBF4B, and EFTUD2.

Data availability

The GWAS summary statistics were deposited in the GWAS catalog: (ftp://ftp-private.ebi.ac.uk/SummaryStatsUploads/XintongWei_prePMID/); The 1KG phase 3 reference panel can be download at: (ftp://ftp.1000genomes.ebi.ac.uk/vol1/ftp/release/20130502/). Online tools: Qtlizer: (http://genehopper.de/qtlizer); HaploReg v4.1: (http://pubs.broadinstitute.org/mammals/haploreg/haploreg.php); STRING: (https://string-db.org/); Gene Atlas: (http://geneatlas.roslin.ed.ac.uk/); PathCards: (https://pathcards.genecards.org/).

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Acknowledgements

We appreciate all the volunteers who participated into this study. YFP and LZ were partially supported by the funding from national natural science foundation of China (31771417 and 31571291). RH was supported by the Medical Health Research Program of Inner Mongolia Autonomous Region Health Commission (201702180). HWD and HS were partially supported by the National Institutes of Health (R01 AR069055, U19 AG055373, R01 MH104680, R01 AR059781, and P20 GM109036), the Franklin D. Dickson/Missouri Endowment and the Edward G. Schlieder Endowment. This study was benefited from a project funded by the Priority Academic Program Development (PAPD) of Jiangsu higher education institutions. The numerical calculations in this paper have been done on the supercomputing system of the National Supercomputing Center in Changsha. The funders had no role in study design, data collection and analysis, results interpretation, or preparation of the manuscript. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (Contract No. N01-HC-25195). This manuscript was not prepared in collaboration with investigators of the Framingham Heart Study and does not necessarily reflect the opinions or views of the Framingham Heart Study, Boston University, or NHLBI. Funding for SHARe Affymetrix genotyping was provided by NHLBI Contract N02-HL-64278. SHARe Illumina genotyping was provided under an agreement between Illumina and Boston University. Funding support for the Framingham Whole Body and Regional Dual X-ray Absorptiometry (DXA) dataset was provided by NIH grants R01 AR/AG 41398. The datasets used for the analyses described in this manuscript were obtained from dbGaP through dbGaP accession phs000342.v14.p10. The WHI program is funded by the National Heart, Lung, and Blood Institute, National 20 Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed and/or approved by the Women’s Health Initiative (WHI), and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. Funding for WHI SHARe genotyping was provided by NHLBI Contract N02-HL-64278. The datasets used for the analyses described in this manuscript were obtained from dbGaP through dbGaP accession phs000200.v10.p3. Funding support for the Genetic Determinants of Bone Fragility (the Indiana fragility study) was provided through the NIA Division of Geriatrics and Clinical Gerontology. Genetic Determinants of Bone Fragility is a genome-wide association studies funded as part of the NIA Division of Geriatrics and Clinical Gerontology. Support for the collection of datasets and samples were provided by the parent grant, Genetic Determinants of Bone Fragility (P01-AG018397). Funding support for the genotyping which was performed at the Johns Hopkins University Center for Inherited Diseases Research was provided by the NIH NIA. The datasets used for the analyses described in this manuscript were obtained from dbGaP through dbGaP accession phs000138.v2.p1.

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Wei, XT., Feng, GJ., Zhang, H. et al. Pleiotropic genomic variants at 17q21.31 associated with bone mineral density and body fat mass: a bivariate genome-wide association analysis. Eur J Hum Genet (2020). https://doi.org/10.1038/s41431-020-00727-3

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